Cardiovascular Drugs and Therapy

, Volume 15, Issue 3, pp 211–218

Safety of HMG-CoA Reductase Inhibitors: Focus on Atorvastatin

  • Franco Bernini
  • Andrea Poli
  • Rodolfo Paoletti
Article

Abstract

Statins effectively lower LDL-cholesterol and some members of this class have been shown to reduce the risk of major cardiovascular events and total mortality in patients with or at risk for coronary heart disease. Statins are in general well tolerated. Withdrawal rates related to adverse events are low (≤3%). The most common adverse events are mild gastrointestinal symptoms. Elevated serum transaminase levels occur infrequently (≤1.5%). These are generally asymptomatic, reversible and rarely require drug withdrawal. Statins do not cause adverse endocrine effects, do not alter glycemic control in diabetic patients, and do not increase cancer risk. Dose-related myopathy and/or rhabdomyolysis also occurs very rarely, although the risk is increased by concomitant administration of cyclosporine, niacin, fibrates, or by CYP3A4 isoenzyme inhibitors (e.g. erythromycin, systemic azole antifungal agents etc.) with statins metabolized by this isoenzyme. The pharmacokinetics of the individual statin should be considered in patients receiving polypharmacological treatments, to minimize the risk of unfavorable drug interactions. Atorvastatin is well tolerated in long-term treatment of dyslipidemia and is characterized by a safety profile similar to the other available statins.

HMG-CoA reductase inhibitors atorvastatin hypercholesterolemia adverse effects drug interactions 

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References

  1. 1.
    National Cholesterol Education Program. Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). Circulation 1994; 89 (3): 1333-1445.Google Scholar
  2. 2.
    Wood D, De Backer G, Faergeman O, et al. Prevention of coronary heart disease in clinical practice: Recommendations of the second joint task force of European and other societies on coronary prevention. Atherosclerosis 1998; 140: 199-270.Google Scholar
  3. 3.
    Shepherd J, Cobbe SM, Ford I, et al. West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333 (20): 1301-1307.Google Scholar
  4. 4.
    Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/ TexCAPS. Air Force/Texas coronary atherosclerosis prevention study. JAMA 1998; 279 (20): 1615-1622.Google Scholar
  5. 5.
    Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin survival study (4S). Lancet 1994; 344 (8934): 1383-1389.Google Scholar
  6. 6.
    Sacks FM, Pfeffer MA, Moye LA, et al. Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335 (14): 1001-1009.Google Scholar
  7. 7.
    Lea AP, McTavish D. Atorvastatin: A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs 1997; 53 (5): 828-847.Google Scholar
  8. 8.
    Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998; 81 (5): 582-587.Google Scholar
  9. 9.
    Black DM, Bakker-Arkema RG, Nawrocki JW. An overview of the clinical safety profile of atorvastatin (Lipitor), a new HMG-CoA reductase inhibitor. Arch Intern Med 1998; 158 (6): 577-584.Google Scholar
  10. 10.
    Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988; 62 (15): 28J-34J.Google Scholar
  11. 11.
    Plosker GL, McTavish D. Simvastatin: A reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolaemia. Drugs 1995; 50 (2): 334-363.Google Scholar
  12. 12.
    Haria M, McTavish D. Pravastatin:Areappraisal of its pharmacological properties and clinical effectiveness in the management of coronary heart disease. Drugs 1997; 53 (2): 299-336.Google Scholar
  13. 13.
    Jokubaitis LA. Updated clinical safety experience with fluvastatin. Am J Cardiol 1994; 73 (14): 18D-24D.Google Scholar
  14. 14.
    McClellan KJ, Wiseman LR, McTavish D. Cerivastatin. Drugs 1998; 555 (3): 415-420.Google Scholar
  15. 15.
    Leiter LA, Hanna K. Efficacy and safety of cerivastatin in primary hypercholesterolemia: A long term comparative titration study with simvastatin. Canad J Cardiol 1999; 15: 545-555.Google Scholar
  16. 16.
    Blum CB. Comparison of properties of four inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [published erratum appears in. Am J Cardiol 1994; 74(6): 639]. Am J Cardiol 1994;73(14):3D-11D.Google Scholar
  17. 17.
    Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Therapeut 1999; 84: 413-428.Google Scholar
  18. 18.
    Plosker GL, Wagstaff AJ. Fluvastatin: A review of its pharmacology and use in the management of hypercholesterolaemia. Drugs 1996; 51 (3): 433-459.Google Scholar
  19. 19.
    Muck W. Rational assessment of the interaction profile of cerivastatin supports its low propensity for drug interaction. Drugs 1998; 56 (Suppl. 1): 15-23.Google Scholar
  20. 20.
    Quion AV, Jones PH. Clinical pharmacokinetics of pravastatin. Clin Pharmacokinetic 1994; 27: 94-103.Google Scholar
  21. 21.
    Davidson M, McKenney J, Stein E, et al. Atorvastatin Study Group I. Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia. Am J Cardiol 1997; 79 (11): 1475-1481.Google Scholar
  22. 22.
    Bertolini S, Bon GB, Campbell LM, et al. Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia. Atherosclerosis 1997; 130: 191-197.Google Scholar
  23. 23.
    Dart A, Jerums G, Nicholson G, et al. A multicenter, doubleblind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia. Am J Cardiol 1997; 80 (1): 39-44.Google Scholar
  24. 24.
    Marz W, Wollschlager H, Klein G, Neiss A, Wehling M. Safety of low-density lipoprotein cholesterol reduction with atorvastatin versus simvastatin in a coronary heart disease population. Am J Cardiol 1999; 84: 7-13.Google Scholar
  25. 25.
    Lovastatin Study Groups I through IV. Lovastatin 5-year safety and efficacy study. Arch Intern Med 1993; 153 (9): 1079-1087.Google Scholar
  26. 26.
    Jacotot B, Banga JD, Waite R, Peters TK. French-Dutch Fluvastatin Study Group. Long-term efficacy with fluvastatin as monotherapy and combined with cholestyramine (a 156-week multicenter study). AmJ Cardiol 1995; 76 (2): 41A-46A.Google Scholar
  27. 27.
    Stein E. Cerivastatin in primary hyperlipidemia: A multicenter analysis of efficacy and safety. Am J Cardiol 1998; 82(4B): 40J-46J.Google Scholar
  28. 28.
    Stein EA. Extending therapy options in treating lipid disorders. A clinical review of cerivastatin, a novel HMG-CoA reductase inhibitor. Drugs 1998; 56 (Suppl. 1): 25-31.Google Scholar
  29. 29.
    Davignon J, Hanfeld M, Nakaya N, Hunninghake DB, Insull W, Ose L. Clinical efficacy and safety of cerivastatin: Summary of pivotal phase IIb/III studies. Am J Cardiol 1998; 82(4b): J32-J39.Google Scholar
  30. 30.
    Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJP, Stalenhoef AFH. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP): A prospective, randomised, double blind trial. Lancet 2001; 357: 577-581.Google Scholar
  31. 31.
    Bakker-Arkema RG, Nawrocki JW, Black DM. Safety profile of atrovastatintreated patients with low LDL-cholesterol levels. Atherosclerosis 2000; 149: 123-129.Google Scholar
  32. 32.
    Boccuzzi SJ, Keegan ME, Hirsch LJ, Shapiro DR, Plotkin DJ, Mitchel YB. Long term experience with simvastatin. Drug Invest 1993; 5: 135-140.Google Scholar
  33. 33.
    Kornbrust DJ, MacDonald JS, Peter CP, et al. Toxicity of the HMG-coenzymeAreductase inhibitor, lovastatin, to rabbits. J Pharmacol Exp Ther 1989; 248 (2): 498-505.Google Scholar
  34. 34.
    Bradford RH, Shear CL, Chremos AN, et al. Expanded clinical evaluation of lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med 1991; 151 (1): 43-49.Google Scholar
  35. 35.
    Newman TJ, Kassler-Taub KB, Gelarden RT, et al. Safety of pravastatin in long-term clinical trials conducted in the United States. J Drug Dev 1990; 3 (Suppl. 1): 275-281.Google Scholar
  36. 36.
    Moghadasian MH. Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Life Sciences 1999; 65: 1329-1337.Google Scholar
  37. 37.
    Smith PF, Eydelloth RS, Grossman SJ, et al. Myopathy associated with HMG-CoA reductase inhibitors (HMGRIs) and cyclosporin A: Evaluation in a rat model. Eur Heart J 1992; 13 (Suppl. B): 2-6.Google Scholar
  38. 38.
    Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACL study: A randomized controlled trial. JAMA 2001; 285: 1711-1718.Google Scholar
  39. 39.
    Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking atorvastatin with gemfibrozil. Am J Cardiol 1998; 81 (3): 368-369.Google Scholar
  40. 40.
    Norman DJ, Illingworth DR, Munson J, Hosenpud J. Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin [letter]. N Engl J Med 1988; 318 (1): 46-47.Google Scholar
  41. 41.
    East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA. Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation [letter]. N Engl J Med 1988; 318 (1): 47-48.Google Scholar
  42. 42.
    Reaven P, Witztum JL. Lovastatin, nicotinic acid, and rhabdomyolysis [letter]. Ann Intern Med 1988; 109 (7): 597-598.Google Scholar
  43. 43.
    Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990; 264 (1): 71-75.Google Scholar
  44. 44.
    Ballantyne CM, Radovancevic B, Farmer JA, et al. Hyperlipidemia after heart transplantation: Report of a 6-year experience, with treatment recommendations. J Am Coll Cardiol 1992; 19 (6): 1315-1321.Google Scholar
  45. 45.
    Barbir M, Rose M, Kushwaha S, Akl S, Mitchell A, Yacoub M. Low-dose simvastatin for the treatment of hypercholesterolaemia in recipients of cardiac transplantation. Int J Cardiol 1991; 33 (2): 241-246.Google Scholar
  46. 46.
    Yoshimura N, Oka T, Okamoto M, Ohmori Y. The effects of pravastatin on hyperlipidemia in renal transplant recipients. Transplantation 1992; 53 (1): 94-99.Google Scholar
  47. 47.
    Wiklund O, Angelin B, Bergman M, et al. Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia. AmJMed 1993; 94 (1): 13-20.Google Scholar
  48. 48.
    Davignon J, Roederer G, Montigny M, et al. Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemia. Am J Cardiol 1994; 73 (5): 339-345.Google Scholar
  49. 49.
    Jacobson TA, Chin MM, Fromell GJ,,Amorosa LF. Fluvastatin with and without niacin for hypercholesterolemia. Am J Cardiol 1994; 74 (2): 149-154.Google Scholar
  50. 50.
    MacDonald JS, Gerson RJ, Kornbrust DJ, et al. Preclinical evaluation of lovastatin. Am J Cardiol 1988; 62 (15): 16J-27J.Google Scholar
  51. 51.
    Dostal LA, Schardein JL, Anderson JA. Developmental toxicity of the HMG-CoA reductase inhibitor, atorvastatin, in rats and rabbits. Teratology 1994; 50 (6): 387-394.Google Scholar
  52. 52.
    Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol 1996; 10 (6): 439-446.Google Scholar
  53. 53.
    Merck & Co., Westpoint, PA, USA. Mevacor (lovastatin) Product Information. 1996.Google Scholar
  54. 54.
    Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA 1996; 275 (1): 55-60.Google Scholar
  55. 55.
    Gerson RJ, MacDonald JS, Alberts AW, et al. Animal safety and toxicology of simvastatin and related hydroxymethylglutaryl-coenzymeAreductase inhibitors. AmJMed 1989; 87(4A): 28S-38S.Google Scholar
  56. 56.
    Williams GM. Epigenetic effects of liver tumor promoters and implications for health effects. Environ Health Perspect 1983; 50: 177-183.Google Scholar
  57. 57.
    Smith PF, Grossman SJ, Gerson RJ, et al. Studies on the mechanism of simvastatin-induced thyroid hypertrophy and follicular cell adenoma in the rat. Toxicol Pathol 1991; 19 (3): 197-205.Google Scholar
  58. 58.
    Molgard J, Lundh BL, von-Schenck H, Olsson AG. Longterm efficacy and safety of the simvastatin alone and in combination therapy in treatment of hypercholesterolaemia. Atherosclerosis 1991; 91: S21-S28.Google Scholar
  59. 59.
    Parke-Davis, Division of Warner-Lambert Company, Morris Plains, NJ, USA. Lipitor (Atorvastatin Calcium Tablets) Package Insert. 1997.Google Scholar
  60. 60.
    The Long Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with Pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349-1357.Google Scholar
  61. 61.
    Pedersen TR, Wilhelmsen L, Faegerman O, et al. Followup of patients randomised in the Scandinavian Simvastatin survival study (4S) of cholesterol lowering. Am J Cardiol 2000; 86: 257-262.Google Scholar
  62. 62.
    Dobs AS, Sarma PS, Schteingart D. Long-term endocrine function in hypercholesterolemic patients treated with pravastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Metabolism 1993; 42 (9): 1146-1152.Google Scholar
  63. 63.
    Azzarito C, Boiardi L, Zini M, et al. Long-term therapy with high-dose simvastatin does not affect adrenocortical and gonadal hormones in hypercholesterolemic patients. Metabolism 1992; 41 (2): 148-153.Google Scholar
  64. 64.
    Bayer Corporation, West Haven, CT, USA. Baycol (cerivastatin sodium tablets) Package Insert. 1998.Google Scholar
  65. 65.
    Isaacsohn JL, Bakker-Arkema RG, Fayyad R, Whitcomb R, Black DM. Atorvastatin, a new HMG-CoA reductase inhibitor, does not affect glucocorticoid hormones in patients with hypercholesterolemia. J Cardiovasc Pharmacol Ther 1997; 1: 243-250.Google Scholar
  66. 66.
    Bristol-Myers Squibb, Princeton, NJ, USA. Pravachol (pravastatin) Product Information. 1996.Google Scholar
  67. 67.
    Merck & Co., Westpoint, PA, USA. Zocor (simvastatina) Product Information. 1997.Google Scholar
  68. 68.
    Tsuda Y, Satoh K, Kitadai M, Takahashi T, Izumi Y, Hosomi N. Effects of pravastatin sodium and simvastatin on plasma fibrinogen and blood rheology in type II hypercholesterolemia. Atherosclerosis 1996; 122: 225-233.Google Scholar
  69. 69.
    Branchi A, Rovellini A, Sommariva D, Gugliandolo AG, Fasoli A. Effect of three fibrate derivatives and two HMGCoA reductase inhibitors on plasma fibrinogen in patients with primary hypercholestreolemia. Thromb Haemostasis 1993; 70: 241-243.Google Scholar
  70. 70.
    Beige Y, Fuchs J, Snir M, Lurie Y, Green P, Djaldetti M. Lovastatin therapy in heterozygous familial hypercholesterolemic patients: Effect on blood rheology and fibrinogen levels. J Intern Med 1991; 230: 23-27.Google Scholar
  71. 71.
    Wierzbicki AS, Lumb PJ, Semra YK, Crook MA. Effect of atorvastatin on plasma fibrinogen. Lancet 1998; 351: 569-570.Google Scholar
  72. 72.
    Otto C, Schwandt P. More on atorvastatin and fibrinogen (letter). Atherosclerosis 2000; 151: 591-592.Google Scholar
  73. 73.
    Aguilar-Salinas CA, Gomez-Perezb FJ, Posadas-Romerob C, et al. Efficacy and safety of atorvastatin in hyperlipidemic, type 2 diabetic patients. A 34-week, multicenter, open-label study. Atherosclerosis 2000; 152: 489-496.Google Scholar
  74. 74.
    Garg A. Treatment of diabetic dyslipidemia. Am J Cardiol 1998; 81(4A): 47B-51B.Google Scholar
  75. 75.
    Pyorala K, Pedersen TR, Kjekhus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin survival study (4S). Diabetes Care 1997; 20 (4): 614-620.Google Scholar
  76. 76.
    Garnett WR. Interactions with hydroxymethylglutarylcoenzyme A reductase inhibitors. Am J Health Syst Pharm 1995; 52: 1639-1645.Google Scholar
  77. 77.
    Gibson DM, Yang B-B, Abel RB, et al. Effects of hepatic and renal impairment on pharmacokinetics (PK) and pharmacodynamics (PD) of atorvastatin [abstract]. Pharm Res 1996; 13 (Suppl. 9): S428.Google Scholar
  78. 78.
    Stern RH, Yang BB, Horton M, Moore S, Abel RB, Olson SC. Renal dysfunction does not alter the pharmacokinetics or LDL-cholesterol reduction of atorvastatin. J Clin Pharmacol 1997; 37 (9): 816-819.Google Scholar
  79. 79.
    Halstenson CE, Triscari J, DeVault A, Shapiro B, Keane W, Pan H. Single-dose pharmacokinetics of pravastatin and metabolites in patients with renal impairment. J Clin Pharmacol 1992; 32 (2): 124-132.Google Scholar
  80. 80.
    Smith PF, Eydelloth RS, Grossman SJ, et al. HMG-CoA reductase inhibitor-induced myopathy in the rat: Cyclosporine A interaction and mechanism studies. J Pharmacol Exp Ther 1991; 257 (3): 1225-1235.Google Scholar
  81. 81.
    Smit JW, Jansen GH, de Bruin TW, Erkelens DW. Treatment of combined hyperlipidemia with fluvastatin andgemfibrozil, alone or in combination, does not induce muscle damage. Am J Cardiol 1995; 76 (2): 126A-128A.Google Scholar
  82. 82.
    Feher MD, Foxton J, Bank D, Lant AF, Wray R. Long-term safety of statinfibrate combination treatment in the management of hypercholesterolaemia in patients with coronary artery disease. Br Heart J 1995; 74: 14-17.Google Scholar
  83. 83.
    Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, et al. Safety and efficacy of long-term statinfibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol 1997; 80: 608-613.Google Scholar
  84. 84.
    Murdock DK, Murdock AK, Murdock RW, et al. Long-term safety and efficacy of combination gemfibrozil and HMGCoA reductase inhibitors for the treatment of mixed lipid disorders. Am Heart J 1999; 138: 151-155.Google Scholar
  85. 85.
    Arnadottir M, Eriksson LO, Thysell H, Karkas JD. Plasma concentration profiles of simvastatin 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin. Nephron 1993; 65 (3): 410-413.Google Scholar
  86. 86.
    Olbricht C, Wanner C, Eisenhauer T, et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporinetreated kidney graft patients after multiple doses. Clin Pharmacol Ther 1997; 62 (3): 311-321.Google Scholar
  87. 87.
    Regazzi MB, Iacona I, Campana C, et al. Altered disposition of pravastatin following concomitant drug therapy with cyclosporinAin transplant recipients. Transplant Proc 1993; 25 (4): 2732-2734.Google Scholar
  88. 88.
    Goldberg R, Roth D. Evaluation of fluvastatin in the treatment of hypercholesterolemia in renal transplant recipients taking cyclosporine. Transplantation 1996; 62 (11): 1559-1564.Google Scholar
  89. 89.
    Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole [letter]. N Engl J Med 1995; 333 (10): 664-665.Google Scholar
  90. 90.
    Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P. Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin. Clinical Pharmacology and Therapeutics 2000; 68: 391-400.Google Scholar
  91. 91.
    Yang B-B, Siedlik PH, Smithers JA, et al. Atorvastatin pharmacokinetic interactions with other CYP3A4 substrates: Erythromycin and ethinyl estradiol [abstract]. Pharm Res 1996; 13 (Suppl.): S437.Google Scholar
  92. 92.
    Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999; 66: 118-127.Google Scholar
  93. 93.
    Edwards DJ, Bernier SM. Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice. Life Sci 1996; 59: 1025-1030.Google Scholar
  94. 94.
    Kline SS, Harrell CC. Potential warfarin-fluvastatin interaction [letter]. Ann Pharmacother 1997; 31 (6): 790.Google Scholar
  95. 95.
    Stern R, Abel R, Gibson GL, Besserer J. Atorvastatin does not alter the anticoagulant activity of warfarin. J Clin Pharmacol 1997; 37 (11): 1062-1064.Google Scholar
  96. 96.
    Transon C, Leemann T, Vogt N, Dayer P. In vivo inhibition profile of cytochrome P450TB (CYP2C9) by (+/-)-fluvastatin. Clin Pharmacol Ther 1995; 58 (4): 412-417.Google Scholar
  97. 97.
    Walker JF. Simvastatin: The clinical profile. Am J Med 1989; 87 (Suppl. 4A): 44S-46S.Google Scholar
  98. 98.
    Lettieri J, Krol G, Mazzu A, Fiebach MZ, Heller AH. Lack of pharmacokinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor and digoxin [abstract]. Atherosclerosis 1997; 130 (Suppl.): S29.Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Franco Bernini
    • 1
  • Andrea Poli
    • 2
  • Rodolfo Paoletti
    • 2
  1. 1.Institute of Pharmacology and PharmacognosyUniversity of ParmaParmaItaly
  2. 2.Department of Pharmacological SciencesUniversity of MilanoMilanoItaly

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